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Lancet Oncol. 2014 Feb;15(2):201-12. doi: 10.1016/S1470-2045(13)70554-0. Epub 2013 Dec 19.

Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial.

Author information

  • 1University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, UK; National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK. Electronic address: hme22@cam.ac.uk.
  • 2Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
  • 3Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, UK. Electronic address: L.Hiller@warwick.ac.uk.
  • 4Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
  • 5University of Melbourne, Shepparton, VIC, Australia.
  • 6National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; CancerResearch UK Cambridge Institute, Cambridge, UK.
  • 7CancerResearch UK Cambridge Institute, Cambridge, UK.
  • 8Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; Peterborough and Stamford Hospitals NHS Foundation Trust and Cambridge University Hospital NHS Foundation Trust, UK.
  • 9Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, UK.
  • 10Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK.
  • 11Department of Surgery, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK.
  • 12Nottingham City Hospital, Hucknall Road, Nottingham, UK.
  • 13Dorset Cancer Centre, Poole Hospital NHS Trust, Poole, UK.
  • 14Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, UK.
  • 15Breast Oncology Unit, Thomas Guy House, Guys Hospital, St Thomas Street, London, UK.
  • 16Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, UK.
  • 17Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
  • 18Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, UK.
  • 19National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK.
  • 20University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, UK; National Institute for Health Research, Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Hills Road, Cambridge, UK; Department of Oncology, Cambridge Cancer Trials Centre, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK; CancerResearch UK Cambridge Institute, Cambridge, UK.

Abstract

BACKGROUND:

Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine).

METHODS:

In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278).

FINDINGS:

Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection.

INTERPRETATION:

Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer.

FUNDING:

Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.

PMID:
24360787
DOI:
10.1016/S1470-2045(13)70554-0
[PubMed - indexed for MEDLINE]
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